Each issue of Grimm Fairy Tales has two parts: a frame story and a fairy tale. The frame story revolves around Dr. Sela Mathers, a Doctor/Professor of Literature who has been given the ability to help people by showing them fairy tales with a lesson about their life. She struggles with the fact that people ignore her advice and ruin their lives anyway, and begins using her ability to dispense justice instead (see issue #15 "The Three Little Pigs"). Sela's nemesis is Belinda, who has the same ability as Sela but uses it for evil.

The other portion of the story is a twisted version of a classic fairy tale. The fairy tales are often violent and end in depressing ways, warning the readers to change their lives or suffer a similar (sometimes, worse) fate.

It is later revealed that Belinda is working for the Dark One, a Satan-like demon who is seeking to conquer not only Earth, but four other worlds from which the fairy tales come from. The worlds include Wonderland, Oz, Neverland, and Myst. The series gradually begins to revolve around Sela herself, as she discovers that she has become a major player in an ancient war between the Dark Horde, led by the Dark One and his allies, and the Guardians, leaders of the worlds the Dark One seeks to conquer. Already Wonderland and Neverland have fallen and are now ruled by the Dark One's allies, the monstrous Jabberwocky and the soul-devouring immortal Pan, respectively.

Starting in May 2007, a Grimm Fairy Talesspin-off and limited series called Return to Wonderland debuted. Written by Raven Gregory, the series tells the tale of Alice Liddle, the heroine of Alice's Adventures in Wonderland, and her teenage daughter, Calie Liddle (an anagram of "Alice").[5] Alice is no longer the little girl who fell down the rabbit hole and discovered Wonderland. Now an adult, she once tried to commit suicide by slitting her wrists. Mentally disturbed and in a dream-like state, her only link to reality is the disturbing white rabbit that she clings to. Calie, not wanting to deal with her mother's mental illness, is now a substance-abusing, alcoholic, promiscuous party girl. The series will deal with the entire Liddle family, Alice's childhood, and Calie venturing into a darker and more frightening Wonderland than the one her mother knows. Confirmed characters for Return to Wonderland are the Queen of Hearts, the Mad Hatter,[6] the Caterpillar, the Carpenter, the Walrus, Tweedledee, Tweedledum, the Cheshire Cat, the Jabberwocky, the March Hare, and the Cook.

Tales From Wonderland, a three part prequel to the Return to Wonderland series, was released in 2008, which included The Queen of Hearts, Alice, and The Mad Hatter, followed in June by #0 of Beyond Wonderland, the sequel to Return to Wonderland.[7][8] The series is expected to return for a third time in the summer of 2009 with another sequel Escape from Wonderland and Tales From Wonderland Series 2, which includes The Cheshire Cat, The Red Queen, Tweedledum and Tweedledee, and The Mad Hatter #2.

Zenescope has now released a 2009 Annual For Wonderland entitled "The House of Liddle", and continued the story of Calie in Beyond Wonderland, Escape From Wonderland, as well as an annual for 2010, 2011, 2012. Recently Zenescope has begun publishing an Ongoing Wonderland Series, as well as the Upcoming Madness of Wonderland; Both of which revolve around Calie and her teenage daughter Violet.

The contents of a Grimm Fairy Tales comic collection can be defined into three categories: there are those issues that are "officially" reprinted in the collection (these issues have their original covers included in the cover gallery section), there are (parts of) issues from another series (these are included to induce the reader to buy that series), and there are bonus stories (original stories that were made specifically for the collection).